PLoS computational biology, 2012-10, Vol.8 (10), p.e1002710-e1002710
2012
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- Autor(en) / Beteiligte
- Titel
- Molecular mechanism for the dual alcohol modulation of Cys-loop receptors
- Ist Teil von
- PLoS computational biology, 2012-10, Vol.8 (10), p.e1002710-e1002710
- Ort / Verlag
- United States: Public Library of Science
- Erscheinungsjahr
- 2012
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Cys-loop receptors constitute a superfamily of pentameric ligand-gated ion channels (pLGICs), including receptors for acetylcholine, serotonin, glycine and γ-aminobutyric acid. Several bacterial homologues have been identified that are excellent models for understanding allosteric binding of alcohols and anesthetics in human Cys-loop receptors. Recently, we showed that a single point mutation on a prokaryotic homologue (GLIC) could transform it from a channel weakly potentiated by ethanol into a highly ethanol-sensitive channel. Here, we have employed molecular simulations to study ethanol binding to GLIC, and to elucidate the role of the ethanol-enhancing mutation in GLIC modulation. By performing 1-µs simulations with and without ethanol on wild-type and mutated GLIC, we observed spontaneous binding in both intra-subunit and inter-subunit transmembrane cavities. In contrast to the glycine receptor GlyR, in which we previously observed ethanol binding primarily in an inter-subunit cavity, ethanol primarily occupied an intra-subunit cavity in wild-type GLIC. However, the highly ethanol-sensitive GLIC mutation significantly enhanced ethanol binding in the inter-subunit cavity. These results demonstrate dramatic effects of the F(14')A mutation on the distribution of ligands, and are consistent with a two-site model of pLGIC inhibition and potentiation.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1553-7358, 1553-734XeISSN: 1553-7358DOI: 10.1371/journal.pcbi.1002710Titel-ID: cdi_plos_journals_1313184430
- Format
- –
- Schlagworte
- Alcohol, Alcohols, Biology, Caenorhabditis elegans Proteins - chemistry, Caenorhabditis elegans Proteins - genetics, Caenorhabditis elegans Proteins - metabolism, Chemistry, Chloride Channels - chemistry, Chloride Channels - genetics, Chloride Channels - metabolism, Computer simulation, cysteine loop ligand gated ion channel receptor, Cysteine Loop Ligand-Gated Ion Channel Receptors - chemistry, Cysteine Loop Ligand-Gated Ion Channel Receptors - genetics, Cysteine Loop Ligand-Gated Ion Channel Receptors - metabolism, Ethanol, Ethanol - chemistry, Ethanol - metabolism, Gene mutations, Genetic aspects, glycine receptor, Health aspects, Ion channels, ligand gated ion channel, Ligands, Lipid Bilayers - chemistry, Models, Biological, Molecular biology, Molecular Dynamics Simulation, Mutation, Phosphatidylcholines - chemistry, Physiological aspects, Protein Binding, Protein Conformation, Reproducibility of Results, Water - chemistry